Our long-term goal is to develop vaccines and antiviral treatments for Ebolavirus infections. We have developed biologically contained Ebolaviruses that protect mice against challenge with a lethal dose of mouse-adapted Ebolavirus. In Aim 1, we plan to test the protective efficacy of these Ebolaviruses in guinea pigs and nonhuman primates. Towards drug development, we have established three different highthroughput screening systems that allow screening in BSL-2 containment. In Aim 2, we propose to conduct high-throughput screening and to optimize lead compounds. The lack of effective preventive or therapeutic treatments for Ebolavirus infections is partly due to the lack of knowledge of cellular genes involved in Ebolavirus replication. Our pilot study demonstrated the potential of siRNA screening approaches to identify such genes; therefore, we plan to conduct siRNA screening of commercially available human siRNA libraries to identify critical genes for the Ebolavirus life cycle (Aim 3). Candidate genes/gene products will then be characterized to elucidate the mechanism(s) by which they interfere with Ebolavirus replication. Studies in Aim 3 may thus suggest novel approaches to the treatment of Ebolavirus infections.